The long-term objective of this application is to develop a MASP-2 blocking monoclonal antibody as a therapeutic agent to prevent and treat complications of diabetes, namely diabetic nephropathy (DN). DN is the leading cause of end stage renal disease, resulting in significant morbidity and mortality and in a major health care burden with medical costs projected to reach $12 billion per year in 2010. Considering a steadily increasing incidence of diabetes and the absence of an effective treatment, DN represents a major unmet medical need of significant commercial potential. The pathogenesis of DN is incompletely understood. Clinical studies suggest a critical role for the lectin pathway of the complement system in DN. Diabetics with low lectin pathway activity have better clinical outcomes and increased long-term survival compared to diabetics with high lectin pathway activity, suggesting that therapeutics that inhibit the lectin pathway may prevent or slow the progression of DN. The MBL- associated protease 2 (MASP-2), an enzyme unique to the lectin pathway and required for its function, has been targeted for therapeutic intervention in the current application. Selective lectin pathway blockade in vivo has been accomplished using MASP-2 knockout mice or mice treated with anti-MASP-2 monoclonal antibody. These treatments have revealed beneficial effects in mouse models of reperfusion injury, transplantation and macular degeneration. We now propose to examine the therapeutic hypothesis that MASP-2 blockade may also be useful in the treatment of renal complications of diabetes. This hypothesis will be tested using db/db mice, an established model of type II diabetes with well-characterized renal complications. Mice will be treated with anti-MASP-2 antibody or isotype control, and effects of antibody treatment on albuminuria, renal function and histological features of DN will be assessed. The therapeutic effects of anti- MASP-2 antibody treatment will be further studied in eNos deficient db/db mice which develop diabetes, hypertension and more advanced pathological features of DN. Successful demonstration of efficacy in these models of diabetic kidney disease will provide compelling rationale to explore anti-MASP-2 antibodies as a novel therapeutic in patients with diabetic kidney disease. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy is the leading cause of end stage renal failure, resulting in significant morbidity and mortality and costs for medical care approaching $12 billion per year. Currently there is no effective treatment available. The objective of this proposal is to develop anti-MASP-2 monoclonal antibodies which specifically block the lectin pathway of the complement system as a novel therapeutic to prevent and treat the renal complications of diabetes.